Abstract
Several thiazolidinedione derivatives having 5-hydroxy-2,3-dihydro-2, 2,4,6,7-pentamethylbenzofuran moieties and their 5-benzyloxy derivatives and 5-hydroxy-2,4,6,7-tetramethylbenzofuran moieties were synthesized and evaluated in db/db mice. Insertion of an N-Me group into the linker between thiazolidinedione and substituted benzofuran pharmacophores showed considerable improvement in their euglycemic activity. Further improvement has been observed when a pyrrolidine moiety is introduced in the structure to give 5-[4-[N-[3(R/S)-5-benzyloxy-2,3-dihydro-2,2,4,6, 7-pentamethylbenzofuran-3-ylmethyl]-(2S)-pyrrolidin-2- ylmethoxy]pheny lene]thiazolidine-2,4-dione (21a). At a 100 mg/kg/day dose of the maleate salt, compound 21a reduced the plasma glucose and triglyceride to the level of lean littermate, i.e. 8 +/- 1 mM, and is the most potent and efficacious compound reported in this series.
MeSH terms
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Animals
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Blood Glucose / metabolism
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Female
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Hypoglycemic Agents / chemical synthesis*
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Hypoglycemic Agents / chemistry
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Hypoglycemic Agents / pharmacokinetics
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Hypoglycemic Agents / pharmacology
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Hypolipidemic Agents / chemical synthesis*
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Hypolipidemic Agents / chemistry
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Hypolipidemic Agents / pharmacokinetics
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Hypolipidemic Agents / pharmacology
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Male
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Mice
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Mice, Inbred C57BL
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Pyrrolidines / chemical synthesis*
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Pyrrolidines / chemistry
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Pyrrolidines / pharmacokinetics
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Pyrrolidines / pharmacology
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Rats
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Rats, Wistar
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Receptors, Cytoplasmic and Nuclear / agonists
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Structure-Activity Relationship
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Thiazoles / chemical synthesis*
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Thiazoles / chemistry
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Thiazoles / pharmacokinetics
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Thiazoles / pharmacology
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Transcription Factors / agonists
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Triglycerides / blood
Substances
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5-(4-(N-(5-benzyloxy-2,3-dihydro-2,2,4,6,7-pentamethylbenzofuran-3-ylmethyl)pyrrolidin-2-ylmethoxy)phenylene)thiazolidine-2,4-dione
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Blood Glucose
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Hypoglycemic Agents
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Hypolipidemic Agents
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Pyrrolidines
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Receptors, Cytoplasmic and Nuclear
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Thiazoles
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Transcription Factors
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Triglycerides